1981/08/19 by Alan Roy Fersht
paper · doi:10.1098/rspb.1981.0044
Abstract The evolution of stable forms of life requires considerable precision in the transfer and utilization of genetic information. The necessary precision is often beyond the limits of even the high specificity expected of enzymes and has been achieved by the coevolution of special enzymic mechanisms that involve the expenditure of some of the energy of the cell. The exquisite fidelity of the genetic coding process is maintained during the replication of DNA and the synthesis of proteins by editing reactions that remove errors. Without these checks, mutation rates would be unacceptably high and proteins largely heterogeneous. The editing mechanisms of amino acid selection during protein synthesis are discussed and used to exemplify the essential features of editing. An incidental result of these studies has been to reveal unexpectedly high binding energies between the side chains of amino acids and the enzymes responsible for their selection. This necessitates a re-evaluation of the forces responsible for the folding and assembly of proteins. The fidelity of DNA replication is now amenable to study by a combination of kinetic and genetic techniques by replicating in vitro DNA from a bacteriophage (ϕX174) and assaying the products by expression in vivo. This has afforded the first measurements of the nature and frequency of the base mispairings that lead to spontaneous mutation. These indicate that the accuracy of Escherichia coli DNA polymerase is the limiting factor determining the rate of spontaneous mutation of the single-stranded DNA bacteriophage. The more accurate replication of the E. coli chromosome requires a post-replicative mismatch repair system, special to double-stranded DNA. A simple relation between the accuracy gained by editing and the cost in terms of the wasteful hydrolysis of the correct products, the cost-selectivity equation, is presented that rationalizes some of the mechanisms and observations.